Maternal periconceptional alcohol consumption and congenital limb deficiencies.

BACKGROUND: Women of childbearing age report high rates of alcohol consumption, which may result in alcohol exposure during early pregnancy. Epidemiological research on congenital limb deficiencies (LDs) and periconceptional exposure to alcohol is inconclusive. METHODS: Data from the National Birth Defects Prevention Study (NBDPS) were examined for associations between LDs and patterns of maternal periconceptional (1 month before conception through the first trimester) alcohol consumption among LD case (n = 906) and unaffected control (n = 8352) pregnancies with expected delivery dates from 10/1997 through 12/2007. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated from unconditional logistic regression analysis for all LDs combined, specific LD subtypes (preaxial/terminal transverse), and LD anatomic groups (upper/lower limbs); interactions with folic acid (FA) supplementation were tested. RESULTS: When compared with nondrinkers, inverse associations were found between all LDs combined, preaxial, and upper LDs and any reported periconceptional alcohol consumption (aORs ranged from 0.56-0.83), drinking without binging (aORs: 0.53-0.75), and binge drinking (≥4 drinks/occasion) (aORs: 0.64-0.94); however, none of the binge drinking aORs were statistically significant. Stratification by alcohol type showed inverse associations between all LDs combined, preaxial, transverse, and upper and lower LDs for drinking without binging of wine only (aORs: 0.39-0.67) and between all LDs combined and upper LDs for drinking without binging of combinations of alcohol (aORs: 0.63-0.87). FA did not modify observed associations. CONCLUSION: Maternal periconceptional alcohol consumption did not emerge as a teratogen for selected LDs in the NBDPS. Future studies should evaluate additional rare LDs among more highly exposed populations.

Self-reported maternal cigarette smoke exposure during the periconceptional period and the risk for omphalocoele.

BACKGROUND: We investigated whether maternal exposure to cigarette smoke was associated with omphalocoele and whether periconceptional folic acid modified the association. METHODS: : We analysed data from the National Birth Defects Prevention Study on omphalocoele case (n = 301) and control (n = 8135) mothers for infants born from 1997 through 2007. Mothers who reported active smoking or exposure to second-hand smoke during the periconceptional period (1 month before conception to 3 months after) were considered exposed. Those who reported use of folic acid supplements during the same period were considered supplement users. Odds ratios and 95% confidence intervals were estimated using multivariable logistic regression adjusted for alcohol use, preconception body mass index, and race/ethnicity. RESULTS: One hundred fifteen (38.2%) case and 2592 (31.9%) control mothers reported exposure to cigarette smoke during the periconceptional period. Adjusted odds ratios [95% confidence intervals] were 1.19 [0.94, 1.53] for any smoke exposure, 0.87 [0.54, 1.40] for active smoking, 1.38 [1.00, 1.90] for second-hand smoke exposure, and 1.16 [0.80, 1.67] for both exposures combined. No dose-response relationship was observed. Folic acid-containing supplements did not reduce the risk for omphalocoele among women with active or second-hand smoke exposure. CONCLUSIONS: Self-reported active maternal smoking, with or without exposure to second-hand smoke, during the periconceptional period was not associated with omphalocoele. In contrast, there was a possible association with periconceptional exposure to second-hand smoke.

Hypospadias and maternal intake of phytoestrogens.

Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007.

PURPOSE: To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants. METHODS: We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year. RESULTS: We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them. CONCLUSIONS: Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility.

Maternal caffeine consumption and risk of congenital limb deficiencies.

BACKGROUND: Animal studies have shown that high doses of caffeine might cause congenital limb deficiencies (LDs); however, no epidemiologic studies have explored this relation. METHODS: This case-control study assessed associations between maternal dietary caffeine and congenital LDs using data from the National Birth Defects Prevention Study (NBDPS), with 844 LD cases and 8069 controls from 1997 to 2007. Caffeine intakes from beverages (coffee, tea, and soda) and chocolate combined and by beverage type were examined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for subtypes of isolated LDs (no additional major anomalies) and LDs with other major anomalies separately, comparing the odds of 10 to <100, 100 to <200, 200 to <300, and 300+ mg/day total caffeine intake to 0 to <10 mg/day. RESULTS: All total dietary caffeine intake categories of 10 mg/day and above were marginally associated with odds of all isolated LDs combined (aOR, 1.4-1.7), isolated longitudinal LDs (aOR, 1.2-1.6), and isolated transverse LDs (aOR, 1.3-1.8) compared to the lowest intake category. A dose-response pattern for total dietary caffeine intake was not observed. CONCLUSIONS: A weak increased risk of congenital LDs associated with maternal dietary caffeine consumption was observed in this study; however, risk did not vary by amount of caffeine consumed.

Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: data from the National Birth Defects Prevention Study, 1997-2003.

BACKGROUND: The association between periconceptional intake of supplements containing folic acid with specific subtypes of limb deficiencies has been inconsistent. The objective was to investigate whether intake of nutrients involved in one-carbon metabolism (folate, vitamin B(6), vitamin B(12), riboflavin, choline, betaine, zinc, and methionine) through diet alone or in combination with a supplement containing folic acid influenced the risk for transverse limb deficiency (TLD) and longitudinal limb deficiency (LLD). METHODS: We analyzed 1997-2003 data from the National Birth Defects Prevention Study and included 324 case infants with TLD, 158 case infants with LLD, and 4982 nonmalformed control infants. A food frequency questionnaire was used to estimate nutrient intakes. Use of supplements containing folic acid 1 month before through 2 months after conception was recorded. RESULTS: Use of a supplement containing folic acid was not associated with LLD or TLD. For nonsupplement users, within (1) the lowest quartile of dietary folate intake or vitamin B(6) intake, adjusted odds ratios (aORs) for LLD were, respectively, 3.86 (95% confidence interval [CI]: 1.08-13.78) and 4.36 (95% CI: 0.93-20.48); and (2) the lowest quartile for riboflavin intake, the aOR for TLD was 2.94 (95% CI: 1.04-8.32). For supplement users within the lowest quartile of folate intake or riboflavin intake, the aORs for TLD were, respectively, 1.52 (95% CI: 0.91-2.54) and 1.54 (95% CI: 1.00-2.37). CONCLUSIONS: TLD and LLD were not associated with supplement use, but TLD was associated with low intakes of riboflavin from diet.

Maternal corticosteroid use and hypospadias.

OBJECTIVE: To explore whether women who reported corticosteroid use during pregnancy were more likely to deliver an infant with hypospadias than women who did not. STUDY DESIGN: The analysis encompassed data on deliveries with an estimated due date between 1997 and 2004 from the National Birth Defects Prevention Study, a large population-based, case-control study conducted in the United States. Included were 1165 cases of moderate to severe hypospadias and 3000 nonmalformed male controls. RESULTS: The mothers of 39 cases (3.3%) and 62 controls (2.1%) reported using a corticosteroid medication during the period extending from 4 weeks before conception to 14 weeks after conception. The odds ratio (OR) for any corticosteroid exposure versus no corticosteroid exposure was 1.6 (95% confidence interval [CI] = 1.1 to 2.5); after adjustment for maternal race/ethnicity, education, age, and study site, it was 1.3 (95% CI = 0.8 to 2.0). Analyses by route of administration and specific component suggest that elevated ORs occurred only for nasal spray/inhaled corticosteroids (OR = 1.5; 95% CI = 0.9 to 2.6). CONCLUSIONS: Maternal use of corticosteroid medications was weakly associated with risk of hypospadias, but the association was negligible after adjustment for potential confounders.

Hypospadias and intake of nutrients related to one-carbon metabolism.

PURPOSE: We examined whether hypospadias is associated with maternal intake of folic acid containing vitamin/mineral supplements or dietary intake of nutrients related to one-carbon metabolism (folate, choline, vitamins B12 and B6, thiamine, riboflavin, methionine and zinc). MATERIALS AND METHODS: The study included births from October 1997 to December 2003 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews. Analyses included 915 cases with second or third degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 2,266 male, liveborn, nonmalformed controls. All ORs and 95% CIs were estimated from logistic regression models that included several potential confounders. Nutrient based analyses also included energy intake. RESULTS: Hypospadias risk was not associated with supplement use (adjusted ORs were 1.2, 95% CI 0.9-1.6 for intake beginning in the month before or the first month of pregnancy and 1.1, 95% CI 0.8-1.4 for intake beginning in the second or third month, relative to no intake). Among women who took supplements reduced hypospadias risk was associated with higher dietary intakes of choline, methionine and vitamin B12. The respective ORs (CIs) for the highest vs lowest quartiles were 0.7 (0.5-1.1), 0.6 (0.4-0.9) and 0.7 (0.5-1.0). Among women who did not take supplements increased risk of hypospadias was associated with higher vitamin B12 intake. The OR (CI) for the highest vs lowest quartile was 3.1 (1.1-9.0). CONCLUSIONS: This study suggests an association of hypospadias with intake of certain nutrients related to one-carbon metabolism.

Vitamin supplements and the risk for congenital anomalies other than neural tube defects.

Randomized trials, supported by many observational studies, have shown that periconceptional use of folic acid, alone or in multivitamin supplements, is effective for the primary prevention of neural tube defects (NTDs). Whether this is true also for other congenital anomalies is a complex issue and the focus of this review. It is useful to consider the evidence not only for specific birth defects separately but, importantly, also for all birth defects combined. For the latter, the Hungarian randomized clinical trial indicated, for periconceptional multivitamin use, a reduction in the risk for all birth defects (odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.35-0.70), even after excluding NTDs (OR = 0.53, 95% CI = 0.38-0.75). The Atlanta population-based case-control study, the only large observational study to date on all major birth defects, also found a significant risk reduction for all birth defects (OR = 0.80, 95% CI = 0.69-0.93) even after excluding NTDs (OR = 0.84, 95% CI = 0.72-0.97). These and other studies also evaluated specific anomalies, including those of the heart, limb, and urinary tract, as well as orofacial clefts, omphalocele, and imperforate anus. For cardiovascular anomalies, two studies were negative, whereas three, including the randomized clinical trial, suggest a possible 25-50% overall risk reduction, more marked for some conotruncal and septal defects. For orofacial clefts, six of seven case-control studies suggest an apparent reduced risk, which could vary by cleft type and perhaps, according to some investigators, by pill dosage. For limb deficiencies, three case-control studies and the randomized trial estimated approximately a 50% reduced risk. For urinary tract defects, three case-control studies and the randomized trial reported reduced risks, as did one study of nonsyndromic omphalocele. All these studies examined multivitamin supplement use. With respect to folic acid alone, a reduced rate of imperforate anus was observed among folic acid users in China. We discuss key gaps in knowledge, possible avenues for future research, and counseling issues for families concerned about occurrence or recurrence of these birth defects.

Trends in neural tube defect prevalence, folic acid fortification, and vitamin supplement use.

In this review, the authors analyze international trends in rates of neural tube defects (NTDs) during the past three decades. Population-based data sources include the Metropolitan Atlanta Congenital Defects Program and other US birth defects surveillance programs in the National Birth Defects Prevention Network, the International Clearinghouse for Birth Defects Monitoring Systems, and US and Canadian vital records. To analyze trends in vitamin consumption, we review data from the US National Health and Nutrition Examination Surveys and international surveys of multivitamin use. We discuss the role of factors associated with historic and continuing declines in NTD rates in most countries. These factors include the introduction and increased utilization of prenatal diagnosis, recommendations for multivitamin use in women of childbearing age, and population-wide increases in blood folate levels that have occurred since food fortification was mandated. We also discuss research needs for further NTD prevention. This is a US government work. There are no restrictions on its use.